Uromodulin (Tamm-Horsfall protein) is the most abundant protein in human urine. It is made exclusively and abundantly in kidney tubules. Its cDNA sequence contains structural motifs often seen in cell adhesion molecules. The abundance, specific location and structural properties of uromodulin have long suggested a role for this protein both in renal physiology (fluid and electrolyte transport and crystal and cytokine binding) and in renal disease (casts of uromodulin are though to participate in the pathogenesis of acute renal failure, especially that associated with rhabdomyolysis and with myeloma). The exact function of uromodulin, however, has remained obscure to date. The objective of studies proposed in this application is to help determine the biological function of uromodulin in health and disease. The specific aim of this application is to produce a uromodulin-deficient strain of mice by the technique of homologous recombination and to study the structure and function of kidneys in the uromodulin-deficient mice for the consequences of uromodulin deficiency.